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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria
E Belnoue1, S M Potter, D S Rosa
1Department of Immunology, Institute Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France.
Abstract:
Previous studies have shown that IFN-gamma is essential for the pathogenesis of cerebral malaria (CM) induced by Plasmodium berghei ANKA (PbA) in mice. However, the exact role of IFN-gamma in the pathway (s) leading to CM has not yet been described. Here, we used 129P2Sv/ev mice which develop CM between 7 and 14 days post-infection with PbA. In this strain, both CD4(+) and CD8(+) T cells were involved in the effector phase of CM. When 129P2Sv/ev mice deficient in the IFN-gamma receptor alpha chain (IFN-gammaR1) were infected with PbA, CM did not occur. Migration of leucocytes to the brain at the time of CM was observed in wild type (WT) but not in deficient mice. However, in the latter, there was an accumulation of T cells in the lungs. Analysis of chemokines and their receptors in WT and in deficient mice revealed a complex, organ-specific pattern of expression. Up-regulation of RANTES/CCL5, IP-10/CCL3 and CCR2 was associated with leucocyte migration to the brain and increased expression of MCP-1/CCL2, IP-10/CCL3 and CCR5 with leucocyte migration to the lung. This shows that IFN-gamma controls trafficking of pathogenic T cells in the brain, thus providing an explanation for the organ-specific pathology induced by PbA infection.
Insights
Interferon-gamma (IFN-gamma) is crucial for cerebral malaria (CM) pathogenesis. This study reveals IFN-gamma controls pathogenic T cell trafficking to the brain, explaining organ-specific pathology in Plasmodium berghei ANKA infection.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium infection.
- Interferon-gamma (IFN-gamma) is implicated in CM pathogenesis, but its precise role is unclear.
- T cells are involved in the effector phase of CM.
Purpose of the Study:
- To elucidate the role of IFN-gamma in the pathways leading to CM.
- To investigate the mechanism by which IFN-gamma influences T cell migration in CM.
- To understand the organ-specific pathology induced by Plasmodium berghei ANKA (PbA) infection.
Main Methods:
- Utilized 129P2Sv/ev mice, susceptible to CM after PbA infection.
- Employed mice deficient in the IFN-gamma receptor alpha chain (IFN-gammaR1).
- Analyzed leukocyte migration to the brain and lungs, and chemokine/receptor expression patterns.
Main Results:
- CM did not develop in IFN-gammaR1-deficient mice infected with PbA.
- Leukocyte migration to the brain was observed in wild-type but not deficient mice.
- T cell accumulation occurred in the lungs of deficient mice, with distinct chemokine profiles for brain vs. lung migration.
Conclusions:
- IFN-gamma is essential for CM development by controlling pathogenic T cell trafficking to the brain.
- The findings explain the organ-specific pathology observed in PbA-induced CM.
- Chemokine and receptor expression patterns are critical for IFN-gamma-mediated leukocyte trafficking in CM.
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